Ten major pathogenic protozoa form a serious threat to the well-being of humankind. There is a desperate need for new medicines for treating infected patients and for use as prophylaxis. The proposed interdisciplinary MSGPP Program Project will accelerate anti-protozoan drug development by: (i) Analyzing the genomes sequences from the targeted protozoa for suitable MSGPP protein targets from a functional and ligand perspective; (ii) Expressing, crystallizing and determining three-dimensional structures of the selected crucial proteins, focusing on complexes with small molecule ligands; (iii) Applying computational processes to these structures to predict new ligands targeting key sites of the selected proteins; (iv) Discovering in solution small molecule ligands binding to target proteins; (v) Using such ligands for the development of new leads and drug candidates, in collaboration with interested institutions. Protein targets will be selected from the following pathogenic protozoa: Plasmodium falciparum, Plasmodium vivax, Trypanosoma brucei, Trypanosoma cruzi, Leishmania major, Leishmania infantum, Entamoeba histolytica, Giardia lamblia, Cryptosporidium parvum, and Toxoplasma gondii. All of these organisms are the subject of ongoing or completed Genome Sequencing Projects. The last four pathogens are BIAID Category B Biodefense organisms. In the course of the three years duration of this Program Project, we estimate to obtain 428 soluble protein variants, representing 183 distinct target proteins, which will result in tree-dimensional structures of around 50 target proteins, plus about 250 target protein structures with ligands bound to them. This MSGPP Program Project includes four tightly integrated Projects and two Cores. We have a unique prior experience, as members of the Structural Genomics of Pathogenic Protozoa (SGPP) consortium, to perform the proposed research.